Eye movements are now widely used as experimental tools in the neurosciences, including studies of memory and volition. The popularity of eye movements derives from their accessibility for measurement and analysis, combined with a broad understanding of their neural substrate. Clinicians mainly depend on basic aspects of gaze control to guide their diagnosis, such as how the brain makes the eyes move together (conjugacy). The proposed research takes aim at several of these basic aspects of the control of eye movements, including properties that are critical for vision to remain clear and single. It also applies one of these basic properties, the conjugacy of horizontal fast movements, to develop a simple model to study the common complaint of fatigue in multiple sclerosis (MS). The research strategy will be to investigate gaze abnormalities by applying and testing current models for the control of eye movements that have been developed from both basic and clinical studies: translational research. The three specific aims grow from work accomplished during the prior funding period: The first project concerns the beginning and ending of rapid eye movements (saccades). The first hypothesis to be tested is that the mechanism generating the beginning of saccades consists of a sudden, stereotyped activation of saccade-generating burst neurons when inhibition is removed from them (post-inhibitory rebound discharge). A second hypothesis is that the ending of saccades is determined by when the cerebellar fastigial nucleus switches firing from excitatory to inhibitory burst neurons. The second project aims to develop an ocular motor model for the phenomenon of fatigue in MS. Preliminary studies indicate that the peak velocity of adducting movements declines relative to the peak velocity of abducting movements during repetitive saccades (a fatigue test) made by MS patients but not by control subjects. The third project aims to better understand a form of acquired nystagmus (oculopalatal tremor) that impairs vision. A current model for these oscillations will be tested using detailed findings from a treatment trial of memantine versus gabapentin completed during the prior funding period. PUBLIC HEALTH RELEVANCE: Taken together, the three proposed projects will provide new information concerning the pathogenesis and treatment of common and visually disabling disorders of eye movements. Eye movements will also be put to work as an experimental tool to investigate the mechanism of generalized fatigue, which afflicts most patients with MS.